Tumor necrosis factor (TNF-α) is a potent cytokine having pro-inflammatory properties that is released by many cell types when stimulated. Studies have shown a relationship between elevated levels of TNF-α and a variety of diseases such as septic shock, hematopoiesis, tumors, and inflammatory disorders of the central nervous system, including HIV encephalitis, cerebral malaria, and meningitis. Certain neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease also are reportedly associated with enhanced TNF-α levels. See, e.g., Arvin et al., “The Role of Inflammation and Cytokines in Brain Injury,” Neuroscience and Biobehavioral Reviews, Vol. 20, No. 3 (1996), at pp. 445-452.
Accordingly, various classes of drugs have been researched and developed to inhibit TNF-α production at both transcriptional and translational levels, e.g., corticosteroids, rolipram (a phosphodiesterase IV inhibitor suppressing TNF-α mRNA synthesis), calphostin, and imidazole-type cytokine suppressing anti-inflammatory drugs (CSAIDs). These drugs are useful in treating a variety of diseases. See Dinarello, “Role of Pro- and Anti-Inflammatory Cytokines During Inflammation: Experimental and Clinical Findings, Review, Vol. 0393-974X (1997), at pp. 91-103.
Recently, attention has focussed on the role of Nuclear factor κB (NF-κB) in the activation pathway that leads to production of TNF-α and other inflammatory cytokines and gene types. Besides TNF-α, NF-κB is involved in the regulation of a variety of genes involved in immune function and inflammation, including IL-2, IL-6, IL-8, IL-2Rα, GM-GSF, intercellular adhesion molecule (ICAM-1), and vascular cellular adhesion molecule-1 (VCAM-1). Thus, inhibition of NF-κB and/or its activation pathway provides a means for treating various diseases including autoimmune diseases, Alzheimer's disease, atherosclerosis, oncogenesis, and so forth. See, e.g., Baldwin, “The NF-κB and lκB Proteins: New Discoveries and Insights,” Annual Rev. Immunol., Vol. 14 (1996), at pp. 649-81; see also Christman et al., “Impact of Basic Research on Tomorrow's Medicine, The Role of Nuclear Factor-κB in Pulmonary Diseases,” Chest, Vol. 117 (2000), at pp. 1482-87.
Potential inhibitors of the NF-κB and/or the NF-κB pathway have been identified as including Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants. IκB is a cytoplasmic protein that controls NF-κB activity by retaining NF-κB in the cytoplasm. IκB is phosphorylated by the lib kinase (IKK), which has two isoforms, IKK-α (“IKK-1”) and IKK-β (“IKK-2”). When IKK phosphorylates IκB, NF-κB is rapidly released from the cytoplasm into the cell. Upon release into the cell, NF-κB translocates to the nucleus where it binds to the promoters of many genes and up-regulates the transcription of pro-inflammatory genes. Glucocorticoids reportedly inhibit NF-κB activity by two mechanisms, i.e., upregulating IκB protein levels and inhibiting NF-κB subunits. Nitric oxide also reportedly inhibits NF-κB through upregulation of IκB. However, these mechanisms of interaction are complex; for example, production of nitric oxide in lymphocytes reportedly enhances NF-κB activity.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness, bioavailability, and solubility, having fewer side effects, and/or providing the consumer with a choice of options. Particularly in the area of immune response, many individuals respond differently depending upon the type of treatment and chemical agent used. Mechanisms of action continue to be studied to aid in understanding the immune response and in developing compounds effective for treating inflammatory and immune-related disorders.
The present invention provides thiophene-based tricyclic compounds useful as inhibitors of IKK. Pyrrolothioenopyrazines having binding affinity for 5-HT3 receptors are disclosed in Rault et al, J. Med. Chem, Vol. 39 (1996), at pp. 2068-80, and European patent application No. 573,360 (Dec. 8, 1993). A broad genus of compounds including certain aromatic-substituted tricyclic thiophenes is disclosed in WO 94/05665 to Neurogen Corp. for use as GABA brain receptor ligands. Polycyclic thiophene compounds are also disclosed in GB Pat. Applic. 2,344,818 to Pharmacia and Upjohn (6/21/00), WO 00/35428 to Boehringer Ingelheim (6/22/00), EP Pat. Applic. 1,104,764 to Hokuriku Seiyaku Co. (Jun. 6, 2001), and Cardoso et al., Bioorg. Med. Chem. Lett., Vol. 12 (2002), at pp. 9-12. AstraZeneca (WO 01/58890, Aug. 16, 2001) reported that certain monocyclic, amide-substituted thiophene compounds may be useful as IKK inhibitors.